NIH Public Access
Author Manuscript
Semin Cell Dev Biol. Author manuscript; available in PMC 2013 September 01.
NIH-PA Author Manuscript
Published in final edited form as:
Semin Cell Dev Biol. 2012 September ; 23(7): 738–744. doi:10.1016/j.semcdb.2012.04.003.
Oxidative stress and adult neurogenesis – effects of radiation
and superoxide dismutase deficiency
Ting-Ting Huang1,2, Yani Zou2, and Rikki Corniola2
1Geriatric Research, Education, and Care Center (GRECC), VA Palo Alto Health Care System,
Palo Alto, CA, USA
2Department
of Neurology and Neurological Sciences, Stanford University School of Medicine,
Stanford, CA, USA
Abstract
NIH-PA Author Manuscript
Hippocampus plays an important role in learning and memory and in spatial navigation.
Production of new neurons that are functionally integrated into the hippocampal neuronal network
is important for the maintenance of functional plasticity. In adults, production of new neurons in
the hippocampus takes place in the subgranular zone (SGZ) of dentate gyrus. Neural progenitor/
stem cells go through processes of proliferation, differentiation, migration, and maturation. This
process is exquisitely sensitive to oxidative stress, and perturbation in the redox balance in the
neurogenic microenvironment can lead to reduced neurogenesis. Cranial irradiation is an effective
treatment for primary and secondary brain tumors. However, even low doses of irradiation can
lead to persistent elevation of oxidative stress and sustained suppression of hippocampal
neurogenesis. Superoxide dismutases (SODs) are major antioxidant enzymes for the removal of
superoxide radicals in different subcellular compartments. To identify the subcellular location
where reactive oxygen species (ROS) are continuously generated after cranial irradiation, different
SOD deficient mice have been used to determine the effects of irradiation on hippocampal
neurogenesis. The study results suggest that, regardless of the subcellular location, SOD
deficiency leads to a significant reduction in the production of new neurons in the SGZ of
hippocampal dentate gyrus. In exchange, the generation of new glial cells was significantly
increased. The SOD deficient condition, however, altered the tissue response to irradiation, and
SOD deficient mice were able to maintain a similar level of neurogenesis after irradiation while
wild type mice showed a significant reduction in the production of new neurons.
NIH-PA Author Manuscript
Keywords
Oxidative stress; cranial irradiation; adult neurogenesis; superoxide dismutase; redox balance;
hippocampus
1. Introduction
Under normal physiological conditions, the production of reactive oxygen species (ROS) in
oxygen utilizing organisms is balanced with the production of reducing equivalents and the
Corresponding author: Ting-Ting Huang, 3801 Miranda Avenue, Building 100, D3-101, Mail stop 154I, Palo Alto, CA 94304 USA,
Phone +1 (650) 496-2581, tthuang@stanford.edu.
Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our
customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of
the resulting proof before it is published in its final citable form. Please note that during the production process errors may be
discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Huang et al.
Page 2
NIH-PA Author Manuscript
removal of ROS by antioxidant defense systems in cells and their surrounding
microenvironment. Although ROS is highly reactive and can cause damages to
macromolecules, production of ROS as by-products during normal metabolic processes is a
necessary trade-off in a not-so-perfect biological system for efficient energy production.
Low levels of ROS are also essential for controlling redox-sensitive proteins involved in
various biochemical reactions, such as growth factor-induced cell proliferation,
differentiation, and survival [1]. Under conditions leading to over-production of ROS or
under-performance of antioxidant defense system, oxidative stress occurs and causes
perturbations in cellular homeostasis. Acute exposure to oxidative stress, such as acute
infections or inflammation and exposure to radiation or redox generating chemicals, leads to
apoptotic cell death, or in extreme cases, necrotic cell death. After removal of the oxidative
stress-inducing agents, cellular homeostasis may be restored. However, in some cases,
chronically elevated levels of oxidative stress can be sustained for a long time. Depending
on the state of redox balance, the altered redox homeostasis can have different effects on
different cellular functions and cell fate decisions. Adult neurogenesis is an important
process to maintain neuronal plasticity and sustain neurocognitive functions, and yet the
neurogenic microenvironment (neurogenic niche) is exquisitely sensitive to oxidative stress
and other types of stresses. This article addresses the role of redox balance in mediating
adult neurogenesis in the context of cranial irradiation and superoxide dismutase (SOD)
deficiency.
NIH-PA Author Manuscript
2. Adult neurogenesis
NIH-PA Author Manuscript
Studies from mice and rats show that new neurons are continuously generated through adult
lives, albeit at a substantially reduced rate as the animals age, in the subgranular zone (SGZ)
of hippocampal dentate gyrus and the subventricular zone (SVZ) of lateral ventricles [2].
Although the sample size was small, Eriksson and colleagues proved that adult humans were
also capable of adult hippocampal neurogenesis by analyzing post-mortem samples from
cancer patients previously injected with bromodeoxyuridine (BrdU) for diagnostic purposes
[3]. In the SGZ of the hippocampus, neural stem cells give rise to neuroblasts, which can
then differentiate and mature. Over the span of several weeks these cells develop axons and
dendritic structures which help them migrate into the granule cell layer and develop granule
cell morphology and markers of mature neurons. It is in the granule cell layer where they
become functionally integrated into the hippocampal network [2]. Similar processes happen
in the SVZ, from which new born cells migrate via the rostral migratory stream to the
olfactory bulb [2]. The combination of cell proliferation, migration, and differentiation are
generally considered to constitute the process of neurogenesis [2]. Within these
microenvironments, proliferating neural progenitor cells are shown to be closely associated
with astrocytes and vascular structures in the SGZ, and it is this close proximity to
microvasculature that is hypothesized to be important for adult neurogenesis [4, 5]. Adult
neurogenesis has been shown to provide the plasticity necessary for the functionally
imperative role that the hippocampus plays in learning, memory and spatial navigation [6–
8]. Consequently, reduction in hippocampal neurogenesis due to pathological changes, or as
a consequence of the normal aging process, reduces the hippocampal function of learning
and memory [9, 10].
3. Redox control of neural stem cell proliferation and differentiation
ROS-mediated activation or suppression of redox-sensitive signaling molecules critical for
cell proliferation and survival have been well established, and the mechanism usually
involves the formation of inter- or intra-molecular disulfide bounds in the cysteine residues
[1]. Through these mechanisms, intracellular redox status has been tied to cell cycle
progression and the decision between proliferation and quiescence in primary fetal
Semin Cell Dev Biol. Author manuscript; available in PMC 2013 September 01.
Huang et al.
Page 3
NIH-PA Author Manuscript
NIH-PA Author Manuscript
fibroblasts [11–13]. Recent studies with precise measurements of the cellular redox status
indicate that a more reduced environment favors cell proliferation, whereas a more oxidized
environment favors cell differentiation [14]. Although the cell fate decision, in terms of
quiescence vs. proliferation and proliferation vs. differentiation, in stem cells is deemed
more complicated, the redox status associated with the fate decision appears to be consistent.
Stem cells are known to maintain a low metabolic status, and the production of ROS is
minimal. As the stem cells are stimulated, either by tissue injury, inflammation, or growth
factors, low levels of ROS are produced, which activates redox-sensitive signaling pathways
that favor cell proliferation [15–19]. Recent in vivo and in vitro studies with neural
progenitor cells suggest that NADPH oxidase activation may be essential for ROS
production, and activation of PI3K/Akt signaling pathway, through oxidative inactivation of
PTEN [18, 19] is responsible for the increased cell proliferation. As the ROS levels increase,
the rate of proliferation slows down and in turn the intracellular environment favors
differentiation (Figure 1). This appears to be true for both neural progenitor cells and glial
precursor cells [17, 19]. In order to achieve neurogenesis, a delicate redox balance needs to
be achieved. Because neural progenitor cells have a choice to differentiate into either
neuronal or astroglia lineage, a recent study suggests that, perhaps within the redox
environment that favors differentiation, a more oxidized environment favors differentiation
towards the astroglia lineage, whereas a more reduced environment favors neuronal lineage
[20]. The lineage decision was shown to be mediated through NAD+ dependent Sirt1
activation [20]. Consequently, perturbation of redox balance within the neurogenic
microenvironment can lead to changes in the production, functional integration, and longterm survival of new neurons.
4. Brain oxidative stress and the antioxidant system
NIH-PA Author Manuscript
The CNS is inherently vulnerable to oxidative stress and the related damages. Brain contains
high levels of polyunsaturated fatty acids (PUFA), particularly arachidonic acid (AA) and
docosahexaenoic acid (DHA). These two PUFAs are the major components of neural cell
membrane phospholipids and are released from cell membranes upon brain injuries.
Enzymatic metabolism of AA by cyclooxygenases (COXs) and lipooxygenase (LOX) leads
to the production of pro-inflammatory mediators, prostaglandins, leukotrienes, and
thromboxanes [21], while non-enzymatic process of AA generates isoprostanes and 4hydroxynonenal (4-HNE). These mediators eventually lead to more production of reactive
oxygen species (ROS), and consequently, higher levels of lipid peroxidation and oxidative
damage [21]. Glutamate is the major excitatory neurotransmitter in the brain. Its release and
uptake is tightly regulated because excessive amount of glutamate is toxic to cells. Under
pathological conditions, abnormally high levels of glutamate can be present in the nervous
system, leading to over activation of glutamate receptors, influx of Ca+2 into neurons, over
production of ROS in the mitochondria, and eventually neuronal cell death [22]. The
heightened vulnerability to oxidative stress in the nervous system is further amplified by the
high energy demand for neuronal functions such as axonal transport and synaptic
transmission. However, neurons have limited glycolytic capacity and mainly rely on
oxidative phosphorylation for energy generation [23, 24]. Consequently, perturbation in
energy metabolism, such as mitochondrial damage or oxygen and glucose deprivation, can
easily lead to neuronal death or dysfunction.
The antioxidant system in the brain is probably sufficient and adequate under normal
conditions. However, contrary to the higher degree of vulnerability in the mitochondria, the
expression levels of brain antioxidant enzymes appear to be higher in the cytosolic
compartment, and are usually ~10 times lower in the mitochondria [25, 26]. Consequently,
deficiency in certain antioxidant enzymes in the nervous system leads to mitochondrial
defects and neuronal degeneration in experimental animals. Examples include the
Semin Cell Dev Biol. Author manuscript; available in PMC 2013 September 01.
Huang et al.
Page 4
NIH-PA Author Manuscript
mitochondrial degeneration and vacuolar degeneration in the brain caused by ubiquitous
deletion of Mn superoxide dismutase (MnSOD) [27, 28]; and, increased lipid peroxidation
and neural degeneration caused by neuronal-specific deletion [29] or inducible deletion [30]
of glutathione peroxidase 4 (Gpx4) in mouse models.
5. Radiation therapy
NIH-PA Author Manuscript
Radiation therapy is used as an adjunct to surgery and chemotherapy in cancer treatments.
The high energy protons generated by ionizing radiation mainly leads to ejection of
electrons from water molecules via hydrolysis in biological systems where water is abundant
(eq 1) [31]. In the presence of oxygen, the free electrons interact with oxygen and form
superoxide radicals (O2•−) (eq 2). Superoxide radicals then cascade down to generating
H2O2 via enzymatic or spontaneous dismutation. H2O2 in turn generates hydroxyl radicals
(OH•−) via Fenton reaction or Haber-Weiss reaction [32, 33]. Collectively, the effect of
irradiation can be viewed as imposing oxidative stress on the biological system. Most
reactive radicals generated by ionizing radiation are disruptive, but short-lived, and the
immediate effects from radiation exposure are double-strand DNA breaks and apoptotic cell
death. This acute phase usually lasts 48 to 72 hours. The production of H2O2 and the
downstream changes in redox-sensitive signaling pathways, on the other hand, can last for
months and sometimes years after the initial irradiation. Persistently elevated oxidative
stress of up to 80 generations of cell doubling has been demonstrated in vitro with cells
treated with 10 Gy of x-ray irradiation [34]. Similarly, markers for oxidative damage can be
detected in tissues months after the initial irradiation [35]. The sustained elevation of ROS in
tissues and cells leads to a shift in the redox homeostasis which could alter the course of cell
proliferation, differentiation, and long-term survival.
(eq 1)
(eq 2)
6. Central nervous system (CNS) and cranial irradiation
NIH-PA Author Manuscript
Exposure of CNS to high levels of ionizing radiation usually happens in the clinics where
patients with primary or secondary brain tumors receive cranial irradiation following
surgical resection. Cranial irradiation has also been used as a prophylactic treatment for
patients with small cell lung carcinoma and breast cancer to prevent metastasis to the brain.
Therapeutic radiation of the brain can cause severe damage to normal tissues if high dose,
large fraction size, and large field size are used [36]. With the improvement of technology
and limited fraction size, overt tissue damage can be avoided. However, deficits in the
neurocognitive functions, including verbal and short-term memory recall, learning, memory,
and spatial processing, and severe dementia, persists [36–38]. Although some deficits can be
observed within the first few months following irradiation therapy, most deficits occur
several months to years later. The toll on the quality of life on the patients and their care
takers can be enormous.
Semin Cell Dev Biol. Author manuscript; available in PMC 2013 September 01.
Huang et al.
Page 5
NIH-PA Author Manuscript
Symptoms of the neurocognitive deficits point to hippocampus as the main target of
radiation-induced tissue damage. The precise mechanism leading to radiation-induced
cognitive dysfunction is not clear; however, clinical evidence from the past point to vascular
damage and the subsequent hypoxic and ischemic damage to the hippocampal formation
[39]. More recently, experimental evidence suggests that damage to neural stem cells and
suppression of neurogenesis after radiation therapy are the most immediate and persistent
events, followed by a late onset of demyelination [40, 41]. Damage to the vasculatures
appears to be a very late event [40]. Studies from mice and rats suggest that neural
progenitor cells from the SGZ of hippocampal dentate gyrus are exquisitely sensitive to
irradiation, which causes a prolonged and dose-related reduction of overall cell proliferation
and the production of new neurons in the SGZ [42, 43]. Persistent inflammation and
activation of reactive microglia may be responsible for the sustained suppression of
neurogenesis, and long-term treatment with indomethacin, a non-steroidal anti-inflammatory
drug, before and after cranial irradiation can partially reduce the suppression of neurogenesis
in experimental mice [44]. Therefore, oxidative stress and sustained alteration of the redox
balance in the neurogenic microenvironment need to be considered as the underlining cause
of irradiation-mediated changes in hippocampal neurogenesis.
7. Superoxide dismutase (SOD, EC 1.15.1.1)
NIH-PA Author Manuscript
NIH-PA Author Manuscript
Superoxide radicals are generated as a by-product of mitochondrial oxidative
phosphorylation and from normal cellular biochemical reactions. Active production of O2•−
is also achieved by activation of NADPH oxidases [45]. In addition, ionizing radiation and a
number of redox-cycling chemicals can produce overwhelming amounts of O2•− in cells
within a short time [46–48]. Over production of O2•− can lead to wide spread damage, and
superoxide dismutases are the first line defense against O2•− in cells and tissues. In
mammals, there are three types of superoxide dismutases (SODs) with different subcellular
distributions, and each encoded by a different gene. The three mammalian SODs are the
cytosolic Cu and Zn containing superoxide dismutase (CuZnSOD), the mitochondrial Mn
containing superoxide dismutase (MnSOD), and the extracellular Cu and Zn containing
superoxide dismutase (EC-SOD). The genetic and biochemical characteristics of each
enzyme are listed in Table 1. Regardless of their subcellular distribution and the metal cofactors, SODs catalyze the dismutation of superoxide radicals into hydrogen peroxide (eq 3),
which is then converted into water by catalase, glutathione peroxidase, or peroxiredoxin (eq
4). The reaction rate constant for each enzyme is in the 109M−1S−1 range at physiological
pH [49]. CuZnSOD and EC-SOD are sensitive to inactivation by cyanide (CN), and the
difference in CN sensitivity allows the measurement of CuZnSOD and MnSOD activities
directly from whole cell or tissue extracts without the need for mitochondrial isolation.
Although the in vivo half life of each SOD has not been determined, SODs are very stable
enzymes, and available data puts the half life in tissues and cells in the range of 70–80 hours
[50–52].
(eq 3)
Semin Cell Dev Biol. Author manuscript; available in PMC 2013 September 01.
Huang et al.
Page 6
(eq 4)
NIH-PA Author Manuscript
Mouse models deficient in each one of the SOD isoforms have been generated and used in
various experimental systems [50, 53–55]. CuZnSOD and EC-SOD null mice (Sod1−/− and
Sod3−/−) are viable and develop normally into adulthood without overt abnormalities. A
subset of CuZnSOD null mice develop hepatocellular carcinoma by 18 months of age, while
EC-SOD null mice appear to have a normal lifespan [56, 57]. MnSOD null mice (Sod2−/−),
on the other hand, suffer from severe mitochondrial damage and metabolic abnormalities
[54]. Consequently, MnSOD null mice, depending on their genetic backgrounds, either die
in mid gestation or survive for up to 3 weeks after birth [27, 28]. Heterozygous CuZnSOD,
MnSOD, and EC-SOD knockout mice (Sod1−/+, Sod2−/+, and Sod3−/+) with 50%
reduction of each SOD, on the other hand, all appear to be healthy with no overt
abnormalities for the majority of their lives under normal laboratory conditions [56, 58].
Transgenic mice with ubiquitous or tissue-specific overproduction of each SOD isoforms
have also been created by several research groups [59–65]. High levels of SOD in cells have
been shown to generate higher levels of H2O2, which can change the redox balance and can
have detrimental effects on cells. However, high levels of CuZnSOD and EC-SOD seem to
be well tolerated by transgenic mice [60, 65]. On the other hand, one transgenic mouse line
with a 10-fold increase in MnSOD was reported to be smaller in size with mitochondrial
defects [61]. In general, overexpression of SOD provides protection against acute oxidative
stress, whereas deficient in SODs render mutant mice more vulnerable to oxidative damage.
NIH-PA Author Manuscript
8. SOD deficiency and hippocampal neurogenesis
NIH-PA Author Manuscript
Change in SOD levels is expected to alter the redox status of neural progenitor cells and
their microenvironment. To examine hippocampal neurogenesis, proliferating cells in the
SGZ can be identified with BrdU incorporation, while lineage-specific markers, NeuN and
GFAP, can be used to identify mature neurons and glia, respectively. Consequently, BrdU+/
NeuN+ cells in the SGZ and granule cell layer can be identified as new-born neurons and
BrdU+/GFAP+ cells as new-born glia. Studies of adult neurogenesis in the SGZ of
heterozygous CuZnSOD and MnSOD knockout mice and EC-SOD null mice showed a
significant, across the board, reduction in the production of new neurons (BrdU+/NeuN+
cells), with the reduction ranging from 35–50% [35, 66]. The data also suggested that
heterozygous CuZnSOD knockout mice had the most severe reduction in neuronal
production, followed in order by EC-SOD null mice and heterozygous MnSOD knockout
mice [35, 66]. Contrary to that finding, the generation of new glial cells (BrdU+/GFAP+)
increased significantly [66], and the largest increase was observed in heterozygous
CuZnSOD knockout mice, followed by heterozygous MnSOD knockout mice. In
comparison, EC-SOD null mice only showed a modest increase in BrdU+/GFAP+ cells [35].
Although more stringent side-by-side comparison will need to be carried out to draw a firm
conclusion, the data suggest that the EC-SOD deficient environment has the least impact on
lineage decision, whereas the CuZnSOD deficient environment has the most impact in
directing progenitor cell differentiation toward the astroglia lineage.
Reduced production of neurons can be due to a reduction in progenitor cell proliferation,
reduction in differentiation into the neuronal lineage, or reduction in the long-term survival
of new-born neurons. Preliminary analysis examining the rate of cell proliferation and the
production of immature neurons (Dcx+, doublecortin positive cells) in the SGZ of EC-SOD
null mice showed that the number of Ki67 and Dcx+ cells were comparable between ECSOD null mice and age-matched wild type controls [35]. The data suggest that the rate of
progenitor cell proliferation and the early stage differentiation into immature neurons was
not altered in EC-SOD null mice and that reduced long-term survival of new-born neurons
may be the cause. Whether the same mechanism applies to CuZnSOD and MnSOD deficient
mice will need to be determined.
Semin Cell Dev Biol. Author manuscript; available in PMC 2013 September 01.
Huang et al.
Page 7
9. Interaction of SOD deficiency and cranial irradiation on hippocampal
neurogenesis
NIH-PA Author Manuscript
Increased oxidative stress during the acute and chronic phase following irradiation is
expected to play a major role in the suppression of hippocampal neurogenesis and the
associated cognitive deficits, and the notion is consistently supported by animal studies [42,
43, 67]. Consequently, animals deficient in SOD are expected to be more sensitive to
irradiation. However, study results from CuZnSOD, MnSOD, and EC-SOD deficient mice
suggested otherwise [35, 66]. Whereas the level of BrdU+ and BrdU+/NeuN+ cells in the
SGZ of irradiated wild type mice were significantly lower than that of non-irradiated
controls at two months after a single dose of 5 Gy cranial irradiation, levels of BrdU+ and
BrdU+/NeuN+ cells in irradiated CuZnSOD, MnSOD, and EC-SOD deficient mice were not
further reduced [35, 66]. Consequently, the levels of neurogenesis in irradiated CuZnSOD,
MnSOD, and EC-SOD deficient mice were higher than irradiated wild type controls. Better
neurogenesis also translated into better cognitive functions in irradiated EC-SOD null mice
as assessed by Morris Water Maze and contextual fear conditioning tests [68].
NIH-PA Author Manuscript
The preserved hippocampal neurogenesis in irradiated SOD deficient mice was unexpected,
and the outcome was not due to up-regulation of other antioxidant enzymes [35, 66]. Study
results from EC-SOD deficient mice, which have the most complete data in hippocampal
neurogenesis and the associated cognitive functions, suggest that the EC-SOD deficient
neurogenic niche perhaps adjusts and returns effectively to a state of redox balance that is
similar to, or a little more reduced than the non-irradiated counterpart during the chronic
phase following irradiation [68]. It is possible that the redox balance in the neurogenic niche
in irradiated wild type controls will eventually return to the same level as its non-irradiated
counterpart; however, the speed at which EC-SOD null mice recover from the disturbance
would be faster, and the mechanism by which a more reduced redox environment is created
may be different between wild type and SOD deficient mice.
10. Conclusion and future studies
NIH-PA Author Manuscript
In summary, oxidative stress and perturbation of redox balance can have significant
consequences in hippocampal neurogenesis and quite possibly, in hippocampal-dependent
function of learning and memory. In patients with primary and secondary brain tumors,
radiation therapy is associated with a high probability of neurocognitive dysfunction long
after the radiation therapy is completed. Antioxidant compounds and other drugs have been
used in experimental animal models with some success to mitigate radiation-mediated
damage to normal tissues [69–77]. However, those approaches may also provide protection
to tumor cells. The SOD deficient system, on the other hand, does not appear to induce a
compensatory up-regulation of other antioxidant enzymes, but at the same time, is able to
restore quickly to a state of redox balance that is favorable for hippocampal neurogenesis
following cranial irradiation. This may be a form of adaptive response or pre-conditioning
due to SOD deficiency.
The mechanism underlies the “adaptive response” is not clear at this stage, but may involve
multiple cell types and modification of the extracellular environment in the neurogenic
niche. It is interesting to point out that CuZnSOD and MnSOD deficient mice all have
significantly elevated levels of BrdU+/GFAP+ cells in the SGZ. Glial cells are known to
produce neurotrophic factors that promote survival of neurons [78–81]. In addition, glial
cells are capable of producing large amounts of GSH, which can facilitate the cystine/
cysteine cycle and provide cysteine to the extracellular space. Neurons can then take up
cysteine for GSH synthesis [82, 83]. Therefore, a larger glial population can ultimately
Semin Cell Dev Biol. Author manuscript; available in PMC 2013 September 01.
Huang et al.
Page 8
support better neuronal survival and provide a better redox buffering capacity under
conditions of oxidative stress.
NIH-PA Author Manuscript
NIH-PA Author Manuscript
To understand the underlying mechanism, it is important to (1) know which cell type(s) in
the neurogenic niche is involved, (2) what factors are important for supporting long-term
survival of the new-born neurons, (3) what signaling pathways are activated and what type
of communication is going on among different cells in the neurogenic niche, and (4) what
may be an effective way to recapitulate the adaptive response in normal tissues to enhance
tissue recovery from radiation therapy. SOD transgenic and knockout mice are available to
allow tissue/cell-specific expression or elimination of SODs. These mouse models will be
helpful in identifying the specific cell types important for providing a favorable environment
for neurogenesis after irradiation and for identifying the signaling pathways and cell
communication involved. Different pharmacological approaches can be taken to temporarily
simulate the SOD-deficient environment. One example would be using heparin, which can
displace EC-SOD from its heparin sulfate or collagen binding site in the extracellular matrix
[84, 85] and creates an EC-SOD deficient environment. The catalytic pocket of SODs is
very small and has hampered the design of specific inhibitors for a long time. However, an
inhibitor of CuZnSOD has been identified recently in a small molecule screen for the
inhibition of lung adenocarcinoma growth [86]. The finding thus opens the possibility for
inhibiting CuZnSOD to temporarily simulate the CuZnSOD deficient environment.
Knowledge on the underlying mechanism of SOD deficiency-induced adaptive response
against radiation-mediated suppression of hippocampal neurogenesis will make it possible to
apply the same principle to the clinical setting to prevent or reduce radiation-mediated
neurocognitive defects in the future. Likewise, detailed knowledge on how redox balance
affect neurogenesis and the associated neurocognitive function will provide the opportunity
to preserve functional neurogenesis during normal aging and under pathological conditions.
Highlights
•
Redox balance affects neural stem cells proliferation and differentiation
•
Redox balance affects the lineage decision of neural stem cells
•
Ionizing radiation induces sustained elevation of oxidative stress in tissues
•
SOD deficiency leads to reduced neurogenesis and increased production of glia
•
SOD deficiency alters irradiation-mediated suppression of hippocampal
neurogenesis
NIH-PA Author Manuscript
Acknowledgments
This work is supported by funding from the National Institutes of Health (NS046051) and the VA Merit Review,
and the facility and resource of VA Palo Alto Health Care System.
Abbreviations
4-HNE
4-hydroxynonenal
AA
Arachidonic acid
BrdU
Bromodeoxyuridine
COX
Cyclooxygenase
DHA
Docosahexaenoic acid
Semin Cell Dev Biol. Author manuscript; available in PMC 2013 September 01.
Huang et al.
Page 9
NIH-PA Author Manuscript
NIH-PA Author Manuscript
CNS
Central nervous system
CuZnSOD
CuZn containing superoxide dismutase
Dcx
Doublecortin
EC-SOD
Extracellular superoxide dismutase
GFAP
Glial fibrillary acidic protein
Gpx4
Glutathione peroxidase 4
LOX
Lipooxygenase
MnSOD
Mn containing superoxide dismutase
NeuN
Neuronal nuclear antigen
PUFA
Polyunsaturated fatty acid
ROS
Reactive oxygen species
SGZ
Subgranular zone
SOD
Superoxide dismutase
SVZ
Subventricular zone
References
NIH-PA Author Manuscript
1. Ray PD, Huang BW, Tsuji Y. Reactive oxygen species (ROS) homeostasis and redox regulation in
cellular signaling. Cell Signal. 2012 [Epublication ahead of print].
2. Ming GL, Song H. Adult neurogenesis in the mammalian central nervous system. Annu Rev
Neurosci. 2005; 28:223–250. [PubMed: 16022595]
3. Eriksson PS, Perfilieva E, Bjork-Eriksson T, Alborn AM, Nordborg C, Peterson DA, Gage FH.
Neurogenesis in the adult human hippocampus. Nat Med. 1998; 4:1313–1317. [PubMed: 9809557]
4. Palmer TD. Adult neurogenesis and the vascular Nietzsche. Neuron. 2002; 34:856–858. [PubMed:
12086632]
5. Palmer TD, Willhoite AR, Gage FH. Vascular niche for adult hippocampal neurogenesis. J Comp
Neurol. 2000; 425:479–494. [PubMed: 10975875]
6. Deng W, Aimone JB, Gage FH. New neurons and new memories: how does adult hippocampal
neurogenesis affect learning and memory? Nat Rev Neurosci. 2010; 11:339–350. [PubMed:
20354534]
7. Bruel-Jungerman E, Rampon C, Laroche S. Adult hippocampal neurogenesis, synaptic plasticity and
memory: facts and hypotheses. Rev Neurosci. 2007; 18:93–114. [PubMed: 17593874]
8. Lledo PM, Alonso M, Grubb MS. Adult neurogenesis and functional plasticity in neuronal circuits.
Nat Rev Neurosci. 2006; 7:179–193. [PubMed: 16495940]
9. Jinno S. Topographic differences in adult neurogenesis in the mouse hippocampus: a stereologybased study using endogenous markers. Hippocampus. 2011; 21:467–480. [PubMed: 20087889]
10. Burger C. Region-specific genetic alterations in the aging hippocampus: implications for cognitive
aging. Front Aging Neurosci. 2010; 2:140. [PubMed: 21048902]
11. Sarsour EH, Kumar MG, Chaudhuri L, Kalen AL, Goswami PC. Redox control of the cell cycle in
health and disease. Antioxid Redox Signal. 2009; 11:2985–3011. [PubMed: 19505186]
12. Menon SG, Goswami PC. A redox cycle within the cell cycle: ring in the old with the new.
Oncogene. 2007; 26:1101–1109. [PubMed: 16924237]
13. Menon SG, Sarsour EH, Spitz DR, Higashikubo R, Sturm M, Zhang H, Goswami PC. Redox
regulation of the G1 to S phase transition in the mouse embryo fibroblast cell cycle. Cancer Res.
2003; 63:2109–2117. [PubMed: 12727827]
Semin Cell Dev Biol. Author manuscript; available in PMC 2013 September 01.
Huang et al.
Page 10
NIH-PA Author Manuscript
NIH-PA Author Manuscript
NIH-PA Author Manuscript
14. Schafer FQ, Buettner GR. Redox environment of the cell as viewed through the redox state of the
glutathione disulfide/glutathione couple. Free Radic Biol Med. 2001; 30:1191–1212. [PubMed:
11368918]
15. Noble M, Mayer-Proschel M, Proschel C. Redox regulation of precursor cell function: insights and
paradoxes. Antioxid Redox Signal. 2005; 7:1456–1467. [PubMed: 16356108]
16. Noble M, Smith J, Power J, Mayer-Proschel M. Redox state as a central modulator of precursor
cell function. Ann N Y Acad Sci. 2003; 991:251–271. [PubMed: 12846992]
17. Smith J, Ladi E, Mayer-Proschel M, Noble M. Redox state is a central modulator of the balance
between self-renewal and differentiation in a dividing glial precursor cell. Proc Natl Acad Sci U S
A. 2000; 97:10032–10037. [PubMed: 10944195]
18. Yoneyama M, Kawada K, Gotoh Y, Shiba T, Ogita K. Endogenous reactive oxygen species are
essential for proliferation of neural stem/progenitor cells. Neurochem Int. 56:740–746. [PubMed:
19958807]
19. Le Belle JE, Orozco NM, Paucar AA, Saxe JP, Mottahedeh J, Pyle AD, Wu H, Kornblum HI.
Proliferative neural stem cells have high endogenous ROS levels that regulate self-renewal and
neurogenesis in a PI3K/Akt-dependant manner. Cell Stem Cell. 8:59–71. [PubMed: 21211782]
20. Prozorovski T, Schulze-Topphoff U, Glumm R, Baumgart J, Schroter F, Ninnemann O, Siegert E,
Bendix I, Brustle O, Nitsch R, Zipp F, Aktas O. Sirt1 contributes critically to the redox-dependent
fate of neural progenitors. Nat Cell Biol. 2008; 10:385–394. [PubMed: 18344989]
21. Phillis JW, Horrocks LA, Farooqui AA. Cyclooxygenases, lipoxygenases, and epoxygenases in
CNS: their role and involvement in neurological disorders. Brain Res Rev. 2006; 52:201–243.
[PubMed: 16647138]
22. Atlante A, Calissano P, Bobba A, Giannattasio S, Marra E, Passarella S. Glutamate neurotoxicity,
oxidative stress and mitochondria. FEBS Lett. 2001; 497:1–5. [PubMed: 11376653]
23. Kasischke KA, Vishwasrao HD, Fisher PJ, Zipfel WR, Webb WW. Neural activity triggers
neuronal oxidative metabolism followed by astrocytic glycolysis. Science. 2004; 305:99–103.
[PubMed: 15232110]
24. Almeida A, Almeida J, Bolanos JP, Moncada S. Different responses of astrocytes and neurons to
nitric oxide: the role of glycolytically generated ATP in astrocyte protection. Proc Natl Acad Sci U
S A. 2001; 98:15294–15299. [PubMed: 11742096]
25. Shmueli O, Horn-Saban S, Chalifa-Caspi V, Shmoish M, Ophir R, Benjamin-Rodrig H, Safran M,
Domany E, Lancet D. GeneNote: whole genome expression profiles in normal human tissues. C R
Biol. 2003; 326:1067–1072. [PubMed: 14744114]
26. Yanai I, Benjamin H, Shmoish M, Chalifa-Caspi V, Shklar M, Ophir R, Bar-Even A, Horn-Saban
S, Safran M, Domany E, Lancet D, Shmueli O. Genome-wide midrange transcription profiles
reveal expression level relationships in human tissue specification. Bioinformatics. 2005; 21:650–
659. [PubMed: 15388519]
27. Huang TT, Carlson EJ, Kozy HM, Mantha S, Goodman SI, Ursell PC, Epstein CJ. Genetic
modification of prenatal lethality and dilated cardiomyopathy in Mn superoxide dismutase mutant
mice. Free Radic Biol Med. 2001; 31:1101–1110. [PubMed: 11677043]
28. Huang TT, Naeemuddin M, Elchuri S, Yamaguchi M, Kozy HM, Carlson EJ, Epstein CJ. Genetic
modifiers of the phenotype of mice deficient in mitochondrial superoxide dismutase. Hum Mol
Genet. 2006; 15:1187–1194. [PubMed: 16497723]
29. Seiler A, Schneider M, Forster H, Roth S, Wirth EK, Culmsee C, Plesnila N, Kremmer E, Radmark
O, Wurst W, Bornkamm GW, Schweizer U, Conrad M. Glutathione peroxidase 4 senses and
translates oxidative stress into 12/15-lipoxygenase dependent- and AIF-mediated cell death. Cell
Metab. 2008; 8:237–248. [PubMed: 18762024]
30. Yoo SE, Chen L, Na R, Liu Y, Rios C, Van Remmen H, Richardson A, Ran Q. Gpx4 ablation in
adult mice results in a lethal phenotype accompanied by neuronal loss in brain. Free Radic Biol
Med. 2012 [Epub ahead of print].
31. Riley PA. Free radicals in biology: oxidative stress and the effects of ionizing radiation. Int J
Radiat Biol. 1994; 65:27–33. [PubMed: 7905906]
32. Liochev SI, Fridovich I. The Haber-Weiss cycle -- 70 years later: an alternative view. Redox Rep.
2002; 7:55–57. author reply 59–60. [PubMed: 11981456]
Semin Cell Dev Biol. Author manuscript; available in PMC 2013 September 01.
Huang et al.
Page 11
NIH-PA Author Manuscript
NIH-PA Author Manuscript
NIH-PA Author Manuscript
33. von Sonntag C. Advanced oxidation processes: mechanistic aspects. Water Sci Technol. 2008;
58:1015–1021. [PubMed: 18824799]
34. Limoli CL, Hartmann A, Shephard L, Yang CR, Boothman DA, Bartholomew J, Morgan WF.
Apoptosis, reproductive failure, and oxidative stress in Chinese hamster ovary cells with
compromised genomic integrity. Cancer Res. 1998; 58:3712–3718. [PubMed: 9721883]
35. Rola R, Zou Y, Huang TT, Fishman K, Baure J, Rosi S, Milliken H, Limoli CL, Fike JR. Lack of
extracellular superoxide dismutase (EC-SOD) in the microenvironment impacts radiation-induced
changes in neurogenesis. Free Radic Biol Med. 2007; 42:1133–1145. discussion 1131–1132.
[PubMed: 17382195]
36. Sarkissian V. The sequelae of cranial irradiation on human cognition. Neurosci Lett. 2005;
382:118–123. [PubMed: 15911133]
37. Laack NN, Brown PD. Cognitive sequelae of brain radiation in adults. Semin Oncol. 2004;
31:702–713. [PubMed: 15497124]
38. Gondi V, Tome WA, Mehta MP. Why avoid the hippocampus? A comprehensive review.
Radiother Oncol. 2010; 97:370–376. [PubMed: 20970214]
39. Abayomi O, Chun MS, Kelly K. Cerebral calcification and learning disabilities following cranial
irradiation for medulloblastoma. J Natl Med Assoc. 1990; 82:833–836. [PubMed: 2280428]
40. Panagiotakos G, Alshamy G, Chan B, Abrams R, Greenberg E, Saxena A, Bradbury M, Edgar M,
Gutin P, Tabar V. Long-term impact of radiation on the stem cell and oligodendrocyte precursors
in the brain. PLoS One. 2007; 2:e588. [PubMed: 17622341]
41. Abayomi OK. Pathogenesis of irradiation-induced cognitive dysfunction. Acta Oncol. 1996;
35:659–663. [PubMed: 8938210]
42. Mizumatsu S, Monje ML, Morhardt DR, Rola R, Palmer TD, Fike JR. Extreme sensitivity of adult
neurogenesis to low doses of X-irradiation. Cancer Res. 2003; 63:4021–4027. [PubMed:
12874001]
43. Monje ML, Mizumatsu S, Fike JR, Palmer TD. Irradiation induces neural precursor-cell
dysfunction. Nat Med. 2002; 8:955–962. [PubMed: 12161748]
44. Monje ML, Toda H, Palmer TD. Inflammatory blockade restores adult hippocampal neurogenesis.
Science. 2003; 302:1760–1765. [PubMed: 14615545]
45. Leto TL, Morand S, Hurt D, Ueyama T. Targeting and regulation of reactive oxygen species
generation by Nox family NADPH oxidases. Antioxid Redox Signal. 2009; 11:2607–2619.
[PubMed: 19438290]
46. Parke DV, Sapota A. Chemical toxicity and reactive oxygen species. Int J Occup Med Environ
Health. 1996; 9:331–340. [PubMed: 9117192]
47. Aust SD, Chignell CF, Bray TM, Kalyanaraman B, Mason RP. Free radicals in toxicology. Toxicol
Appl Pharmacol. 1993; 120:168–178. [PubMed: 8511786]
48. Cohen GM, d'Arcy Doherty M. Free radical mediated cell toxicity by redox cycling chemicals. Br
J Cancer Suppl. 1987; 8:46–52. [PubMed: 2820459]
49. Gray B, Carmichael AJ. Kinetics of superoxide scavenging by dismutase enzymes and manganese
mimics determined by electron spin resonance. Biochem J. 1992; 281(Pt 3):795–802. [PubMed:
1311175]
50. Carlsson LM, Jonsson J, Edlund T, Marklund SL. Mice lacking extracellular superoxide dismutase
are more sensitive to hyperoxia. Proc Natl Acad Sci U S A. 1995; 92:6264–6268. [PubMed:
7603981]
51. Nakano R, Inuzuka T, Kikugawa K, Takahashi H, Sakimura K, Fujii J, Taniguchi N, Tsuji S.
Instability of mutant Cu/Zn superoxide dismutase (Ala4Thr) associated with familial amyotrophic
lateral sclerosis. Neurosci Lett. 1996; 211:129–131. [PubMed: 8830861]
52. Berkovich A, Massaro D, Clerch LB. Pertussis toxin alters the concentration and turnover of
manganese superoxide dismutase in rat lung. Am J Physiol. 1996; 271:L875–L879. [PubMed:
8997256]
53. Huang TT, Yasunami M, Carlson EJ, Gillespie AM, Reaume AG, Hoffman EK, Chan PH, Scott
RW, Epstein CJ. Superoxide-mediated cytotoxicity in superoxide dismutase-deficient fetal
fibroblasts. Arch Biochem Biophys. 1997; 344:424–432. [PubMed: 9264557]
Semin Cell Dev Biol. Author manuscript; available in PMC 2013 September 01.
Huang et al.
Page 12
NIH-PA Author Manuscript
NIH-PA Author Manuscript
NIH-PA Author Manuscript
54. Li Y, Huang TT, Carlson EJ, Melov S, Ursell PC, Olson JL, Noble LJ, Yoshimura MP, Berger C,
Chan PH, Wallace DC, Epstein CJ. Dilated cardiomyopathy and neonatal lethality in mutant mice
lacking manganese superoxide dismutase. Nat Genet. 1995; 11:376–381. [PubMed: 7493016]
55. Lebovitz RM, Zhang H, Vogel H, Cartwright J Jr, Dionne L, Lu N, Huang S, Matzuk MM.
Neurodegeneration, myocardial injury, and perinatal death in mitochondrial superoxide dismutasedeficient mice. Proc Natl Acad Sci U S A. 1996; 93:9782–9787. [PubMed: 8790408]
56. Elchuri S, Oberley TD, Qi W, Eisenstein RS, Jackson Roberts L, Van Remmen H, Epstein CJ,
Huang TT. CuZnSOD deficiency leads to persistent and widespread oxidative damage and
hepatocarcinogenesis later in life. Oncogene. 2005; 24:367–380. [PubMed: 15531919]
57. Sentman ML, Granstrom M, Jakobson H, Reaume A, Basu S, Marklund SL. Phenotypes of mice
lacking extracellular superoxide dismutase and copper- and zinc-containing superoxide dismutase.
J Biol Chem. 2006; 281:6904–6909. [PubMed: 16377630]
58. Van Remmen H, Ikeno Y, Hamilton M, Pahlavani M, Wolf N, Thorpe SR, Alderson NL, Baynes
JW, Epstein CJ, Huang TT, Nelson J, Strong R, Richardson A. Life-long reduction in MnSOD
activity results in increased DNA damage and higher incidence of cancer but does not accelerate
aging. Physiol Genomics. 2003; 16:29–37. [PubMed: 14679299]
59. Epstein CJ, Avraham KB, Lovett M, Smith S, Elroy-Stein O, Rotman G, Bry C, Groner Y.
Transgenic mice with increased Cu/Zn-superoxide dismutase activity: animal model of dosage
effects in Down syndrome. Proc Natl Acad Sci U S A. 1987; 84:8044–8048. [PubMed: 2960971]
60. Tu PH, Raju P, Robinson KA, Gurney ME, Trojanowski JQ, Lee VM. Transgenic mice carrying a
human mutant superoxide dismutase transgene develop neuronal cytoskeletal pathology
resembling human amyotrophic lateral sclerosis lesions. Proc Natl Acad Sci U S A. 1996;
93:3155–3160. [PubMed: 8610185]
61. Raineri I, Carlson EJ, Gacayan R, Carra S, Oberley TD, Huang TT, Epstein CJ. Strain-dependent
high-level expression of a transgene for manganese superoxide dismutase is associated with
growth retardation and decreased fertility. Free Radic Biol Med. 2001; 31:1018–1030. [PubMed:
11595386]
62. Yen HC, Oberley TD, Vichitbandha S, Ho YS, St Clair DK. The protective role of manganese
superoxide dismutase against adriamycin-induced acute cardiac toxicity in transgenic mice. J Clin
Invest. 1996; 98:1253–1260. [PubMed: 8787689]
63. Ho YS, Vincent R, Dey MS, Slot JW, Crapo JD. Transgenic models for the study of lung
antioxidant defense: enhanced manganese-containing superoxide dismutase activity gives partial
protection to B6C3 hybrid mice exposed to hyperoxia. Am J Respir Cell Mol Biol. 1998; 18:538–
547. [PubMed: 9533942]
64. Oury TD, Ho YS, Piantadosi CA, Crapo JD. Extracellular superoxide dismutase, nitric oxide, and
central nervous system O2 toxicity. Proc Natl Acad Sci U S A. 1992; 89:9715–9719. [PubMed:
1329105]
65. Zou Y, Chen CH, Fike JR, Huang TT. A new mouse model for temporal- and tissue-specific
control of extracellular superoxide dismutase. Genesis. 2009; 47:142–154. [PubMed: 19165829]
66. Fishman K, Baure J, Zou Y, Huang TT, Andres-Mach M, Rola R, Suarez T, Acharya M, Limoli
CL, Lamborn KR, Fike JR. Radiation-induced reductions in neurogenesis are ameliorated in mice
deficient in CuZnSOD or MnSOD. Free Radic Biol Med. 2009; 47:1459–1467. [PubMed:
19703553]
67. Fike JR, Rola R, Limoli CL. Radiation response of neural precursor cells. Neurosurg Clin N Am.
2007; 18:115–127. x. [PubMed: 17244559]
68. Raber J, Villasana L, Rosenberg J, Zou Y, Huang TT, Fike JR. Irradiation enhances hippocampusdependent cognition in mice deficient in extracellular superoxide dismutase. Hippocampus. 2011;
21:72–80. [PubMed: 20020436]
69. Carpenter M, Epperly MW, Agarwal A, Nie S, Hricisak L, Niu Y, Greenberger JS. Inhalation
delivery of manganese superoxide dismutase-plasmid/liposomes protects the murine lung from
irradiation damage. Gene Ther. 2005; 12:685–693. [PubMed: 15750616]
70. Epperly M, Bray J, Kraeger S, Zwacka R, Engelhardt J, Travis E, Greenberger J. Prevention of late
effects of irradiation lung damage by manganese superoxide dismutase gene therapy. Gene Ther.
1998; 5:196–208. [PubMed: 9578839]
Semin Cell Dev Biol. Author manuscript; available in PMC 2013 September 01.
Huang et al.
Page 13
NIH-PA Author Manuscript
NIH-PA Author Manuscript
NIH-PA Author Manuscript
71. Epperly MW, Defilippi S, Sikora C, Gretton J, Kalend A, Greenberger JS. Intratracheal injection of
manganese superoxide dismutase (MnSOD) plasmid/liposomes protects normal lung but not
orthotopic tumors from irradiation. Gene Ther. 2000; 7:1011–1018. [PubMed: 10871749]
72. Greenberger JS, Epperly M, Luketich J, Gooding W, Belani CP. Manganese superoxide dismutaseplasmid/liposome (MnSOD-PL) gene therapy protection of the esophagus from
chemoradiotherapy damage during treatment of locally unresectable non-small-cell lung cancer
(NSCLC). Clin Lung Cancer. 2000; 1:302–304. [PubMed: 14733636]
73. Greenberger JS, Epperly MW, Gretton J, Jefferson M, Nie S, Bernarding M, Kagan V, Guo HL.
Radioprotective gene therapy. Curr Gene Ther. 2003; 3:183–195. [PubMed: 12762478]
74. Guo H, Epperly MW, Bernarding M, Nie S, Gretton J, Jefferson M, Greenberger JS. Manganese
superoxide dismutase-plasmid/liposome (MnSOD-PL) intratracheal gene therapy reduction of
irradiation-induced inflammatory cytokines does not protect orthotopic Lewis lung carcinomas. In
Vivo. 2003; 17:13–21. [PubMed: 12655784]
75. Gobbel GT, Marton LJ, Lamborn K, Seilhan TM, Fike JR. Modification of radiation-induced brain
injury by alpha-difluoromethylornithine. Radiat Res. 1991; 128:306–315. [PubMed: 1961928]
76. Fike JR, Gobbel GT, Marton LJ, Seilhan TM. Radiation brain injury is reduced by the polyamine
inhibitor alpha-difluoromethylornithine. Radiat Res. 1994; 138:99–106. [PubMed: 8146307]
77. Fike JR, Gobbel GT, Chou D, Wijnhoven BP, Bellinzona M, Nakagawa M, Seilhan TM. Cellular
proliferation and infiltration following interstitial irradiation of normal dog brain is altered by an
inhibitor of polyamine synthesis. Int J Radiat Oncol Biol Phys. 1995; 32:1035–1045. [PubMed:
7607924]
78. Lindvall O, Wahlberg LU. Encapsulated cell biodelivery of GDNF: a novel clinical strategy for
neuroprotection and neuroregeneration in Parkinson's disease? Exp Neurol. 2008; 209:82–88.
[PubMed: 17963752]
79. Kilic E, Kilic U, Hermann DM. TAT-GDNF in neurodegeneration and ischemic stroke. CNS Drug
Rev. 2005; 11:369–378. [PubMed: 16614736]
80. Wang Y, Chang CF, Morales M, Chiang YH, Hoffer J. Protective effects of glial cell line-derived
neurotrophic factor in ischemic brain injury. Ann N Y Acad Sci. 2002; 962:423–437. [PubMed:
12076993]
81. Alberch J, Perez-Navarro E, Canals JM. Neuroprotection by neurotrophins and GDNF family
members in the excitotoxic model of Huntington's disease. Brain Res Bull. 2002; 57:817–822.
[PubMed: 12031278]
82. Conrad M, Sato H. The oxidative stress-inducible cystine/glutamate antiporter, system x (c) (−) :
cystine supplier and beyond. Amino Acids. 2011
83. Trotti D, Danbolt NC, Volterra A. Glutamate transporters are oxidant-vulnerable: a molecular link
between oxidative and excitotoxic neurodegeneration? Trends Pharmacol Sci. 1998; 19:328–334.
[PubMed: 9745361]
84. Karlsson K, Marklund SL. Heparin-, dextran sulfate- and protamine-induced release of
extracellular-superoxide dismutase to plasma in pigs. Biochim Biophys Acta. 1988; 967:110–114.
[PubMed: 2458767]
85. Karlsson K, Marklund SL. Heparin-induced release of extracellular superoxide dismutase to
human blood plasma. Biochem J. 1987; 242:55–59. [PubMed: 3593249]
86. Somwar R, Erdjument-Bromage H, Larsson E, Shum D, Lockwood WW, Yang G, Sander C,
Ouerfelli O, Tempst PJ, Djaballah H, Varmus HE. Superoxide dismutase 1 (SOD1) is a target for a
small molecule identified in a screen for inhibitors of the growth of lung adenocarcinoma cell
lines. Proc Natl Acad Sci U S A. 2011; 108:16375–16380. [PubMed: 21930909]
87. Millikan RC, Player J, de Cotret AR, Moorman P, Pittman G, Vannappagari V, Tse CK, Keku T.
Manganese superoxide dismutase Ala-9Val polymorphism and risk of breast cancer in a
population-based case-control study of African Americans and whites. Breast Cancer Res. 2004;
6:R264–R274. [PubMed: 15217492]
88. Grasbon-Frodl EM, Kosel S, Riess O, Muller U, Mehraein P, Graeber MB. Analysis of
mitochondrial targeting sequence and coding region polymorphisms of the manganese superoxide
dismutase gene in German Parkinson disease patients. Biochem Biophys Res Commun. 1999;
255:749–752. [PubMed: 10049782]
Semin Cell Dev Biol. Author manuscript; available in PMC 2013 September 01.
Huang et al.
Page 14
NIH-PA Author Manuscript
89. Zhang HJ, Yan T, Oberley TD, Oberley LW. Comparison of effects of two polymorphic variants
of manganese superoxide dismutase on human breast MCF-7 cancer cell phenotype. Cancer Res.
1999; 59:6276–6283. [PubMed: 10626823]
90. Sandstrom J, Nilsson P, Karlsson K, Marklund SL. 10-fold increase in human plasma extracellular
superoxide dismutase content caused by a mutation in heparin-binding domain. J Biol Chem.
1994; 269:19163–19166. [PubMed: 8034674]
91. Yamakura F, Kawasaki H. Post-translational modifications of superoxide dismutase. Biochim
Biophys Acta. 1804:318–325. [PubMed: 19837190]
92. Stromqvist M, Holgersson J, Samuelsson B. Glycosylation of extracellular superoxide dismutase
studied by high-performance liquid chromatography and mass spectrometry. J Chromatogr. 1991;
548:293–301. [PubMed: 1939427]
NIH-PA Author Manuscript
NIH-PA Author Manuscript
Semin Cell Dev Biol. Author manuscript; available in PMC 2013 September 01.
Huang et al.
Page 15
NIH-PA Author Manuscript
Figure 1.
NIH-PA Author Manuscript
Neurogenesis and redox balance. The relationship between the redox status and the process
of neural progenitor cell (NPC) proliferation, differentiation, and maturation is depicted. N,
neuroblasts; Dcx, doublecortin positive cell (immature neuron); NeuN, NeuN+ cell (mature
neuron). The neurogenic niche is depicted at the left as a cluster of NPC, neuroblast,
astrocyte, and microvasculature. At the junction for lineage decision (differentiation), higher
ROS concentration would favor the astroglial lineage and lead to the differentiation and
maturation of glial cells.
NIH-PA Author Manuscript
Semin Cell Dev Biol. Author manuscript; available in PMC 2013 September 01.
Huang et al.
Page 16
Table 1
Genetic and Biochemical properties of mammalian superoxide dismutases
NIH-PA Author Manuscript
CuZnSOD
MnSOD
EC-SOD
Gene designation (human/mouse)
SOD1/Sod1
SOD2/Sod2
SOD3/Sod3
Chromosome location (human/mouse)
HAS 21/MMU16
HAS 6/MMU 17
HAS 4/MMU 5
Polymorphisms/mutations
165 mutations to date1
Val(−9)Ala and Ile(58)Thr [87–
89]
Arg(213)Gly [90]
Disease caused by enzyme defects
Amyotrophic lateral sclerosis
(ALS)
None
None
Metal co-factor(s)
Cu and Zn
Mn
Cu and Zn
Active form
dimer
tetramer
tetramer
Subcellular locations
Cytosol, intermembrane space of
mitochondria, nucleus
Mitochondrial matrix
Extracellular matrix and
circulation
Tissue distribution (from high to low)
Liver, kidney, brain, heart
Heart, brain, skeletal muscle
Blood vessels, lung, kidney,
uterus
Post-translational modification
Nitration, phosphorylation,
glutathiolation, glycation [91]
Acetylation, nitration,
phosphorylation [91]
Glycosylation [92]
1
See ALS online database (ALSoD) http://alsod.iop.kcl.ac.uk/Overview/gene.aspx?gene_id=SOD1
NIH-PA Author Manuscript
NIH-PA Author Manuscript
Semin Cell Dev Biol. Author manuscript; available in PMC 2013 September 01.